Summary: An international team of researchers has reported results of
a study of nervous tissue samples taken from people experiencing active
MS symptoms:

The team identified four distinct categories of MS based on the appearance
and analysis of brain lesions, or areas with myelin destruction;

The investigators suggest that what is called "MS" may be a group of similar
clinical diseases that have different causes, and that individuals with
different types of MS may require different therapies;

To follow up, the National MS Society has launched "The MS Lesion Project,"
a five-year, $1.8 million international research project to correlate clinical
manifestations of MS and findings from MRI and brain tissue samples.

Details: A pathbreaking study of MS brain tissue conducted by an international
team of investigators has identified four distinct categories of multiple
sclerosis (MS), based on the appearance of brain lesions, suggesting there
may be several different mechanisms of myelin destruction in MS. The researchers
speculate that this may mean that what is called "MS" may be a group of
similar clinical diseases that have different causes, and that individuals
with different types of MS may require different therapies. The team, which
includes Hans Lassman, MD (University of Vienna, Austria), Wolfgang Bruck,
MD (Humboldt University, Berlin, Germany) and Claudia Lucchinetti, MD (Mayo
Clinic, Rochester, Minn.), reported its findings in the June issue of Annals
of Neurology.

Background: MS involves an immune-system attack against the insulating
myelin coating of nerve fibers in the brain and spinal cord. The attack
can strip myelin from the nerve fiber and leave a scarred lesion, or "plaque,"
that can be seen on MRI scans. The clinical course and symptoms of MS within
and between individuals can be extremely variable, as is its effects on
nervous tissue, as seen by MRI and other scanning methods. In addition,
people with MS differ in their responses to therapy. Based on these and
other observations, some investigators have suggested that MS may not be
one single disease but a "syndrome" including a number of very similar
diseases that all result in myelin destruction. These are among the reasons
the investigators undertook a study looking at the physical appearance
of actual MS lesions and the immune forces at work in the lesions.

The Study: The researchers examined nervous tissue samples taken from
people experiencing active neurological symptoms. The samples came from
51 individuals who had brain biopsies (a rare procedure sometimes necessary
to exclude other possible diseases) and from 32 individuals who had died
in the midst of MS flare-ups, or relapses. Most of the individuals sampled
were in fairly early stages of disease.

The team analyzed lesions in the brain tissues to determine what type
of immune cells and proteins were present, where and to what extent myelin
was lost, whether specific myelin proteins were absent or present, and
whether myelin-making cells (oligodendrocytes) appeared to be damaged or
dead.

The investigators were able to classify lesions into four different
patterns of myelin destruction. Patterns I and II were similar, but not
identical, in the types of immune activity present, in the absence of all
myelin proteins, in the location of lesions near blood vessels, and in
the presence of oligodendrocytes in the center of lesions. Pattern III
had similar immune activity but lesions were not surrounding blood vessels,
all but one type of myelin protein were still present in damaged myelin,
and there were no oligodendrocytes left in the center of the lesions. Pattern
IV, the most rare, showed immune activity in the lesion, but myelin loss
was associated with oligodendrocyte death in a rim of adjacent, normal-appearing
tissue, with almost a complete loss of oligodendrocytes in active and inactive
lesion areas.

Patterns of lesions were different between individuals, but for a given
indivdidual, multiple lesions had the same pattern. A distinct association
between lesion type and the clinical form of MS was not clear. Pattern
I and II lesions were found in people with all different clinical forms
of MS. However, pattern III lesions were mainly found in individuals who
had had the disease less than two months and pattern IV was found in only
three individuals, all of whom had the primary-progressive form of MS.

What the Study Means: These findings suggest, but do not prove, that
processes that lead to myelin destruction in MS may be different in distinct
subgroups of the disease. This raises the possibility that there may be
different causes for each subgroup, and also suggests that a therapy that
may be effective in individuals with one subgroup of disease may be ineffective,
or even be harmful, in individuals of a different subgroup.

Further research is required to confirm these results in a larger number
of tissue samples and to find non-invasive ways to detect what type of
myelin destruction any individual is experiencing, focusing on magnetic
resonance imaging techniques to understand if MRI characteristics match
the actual lesion pathology seen in tissues, and if both can be more closely
associated with clinical disease type.

To follow up on this important work, the National MS Society just launched
"The MS Lesion Project," a special Society-targeted investigation and the
largest study of its kind to correlate clinical manifestations of MS and
findings from MRI and brain tissue samples. The five-year, $1.8 million
international collaborative research project is being conducted by Dr.
Claudia Lucchinetti at the Mayo Clinic and the other collaborators in the
current study.